MECHANISM AND REGULATION OF RECEPTOR-G PROTEIN SIGNALING

受体-G 蛋白信号传导的机制和调控

• 批准号: 8073842
• 负责人: Kendall J Blumer
• 金额: $ 9.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073842
• 关键词: Address; Adult; Adverse effects; Behavior; Binding; Binding Proteins; Biological Assay; Biology; Bipolar Neuron; Brain; Caenorhabditis elegans; Cell Line; Cell Nucleus; Cell membrane; Cells; Chronic Disease; Cocaine; Complex; Data; Defect; Dendritic Spines; Development; Drug effect disorder; Epilepsy; Event; Family; Family member; Filopodia; Funding; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; GTPase-Activating Proteins; Goals; Grant; Kinetics; Lead; Light; Lipids; Membrane; Mental Depression; Modification; Molecular; Morphine; Morphogenesis; Mus; Nervous system structure; Neuraxis; Neurons; Nuclear; Opioid; Pain; Palmitates; Parkinson Disease; Pharmaceutical Preparations; Phenotype; Phototransduction; Process; Proteins; Publishing; Regulation; Retinal; Role; Signal Transduction; Signaling Protein; Specificity; Structure; Synaptic Transmission; System; Testing; Vertebral column; Vertebrates; Vision; Visual; Xenopus oocyte; addiction; base; dimer; drug efficacy; in vivo; insight; member; neuron development; novel; palmitoylation; postnatal; protein complex; public health relevance; receptor; synaptogenesis; trafficking

DESCRIPTION (provided by applicant): The long-term goal of this project is to define mechanisms that govern signal transduction by G protein-coupled receptors (GPCRs). The focus of the present application is a class of developmentally-regulated, visual and nervous system-specific G23 dimers consisting of G25, the most diverged and least understood G2 family member, bound to the G3-like domain of any member of the RGS7 (R7) family of G protein regulators. R7-G25 heterodimers bind R7BP, a novel palmitoylated SNARE-like protein. The central hypothesis of this application is that palmitate cycling on R7BP controls the localization and function of R7-G25-R7BP complexes as regulators of neuronal structure and function. This project will test this hypothesis by employing interdisciplinary cell, molecular and electrophysiological assays that address the following Specific Aims: 1) identify mechanisms that regulate R7BP palmitate cycling and trafficking in primary neurons; 2) determine how R7BP regulates the ability of R7- G25 complexes to modulate synaptic transmission and the role of palmitoylation in these processes; and 3) identify signaling mechanisms whereby R7-G25-R7BP complexes regulate neuronal development, plasticity and morphogenesis. PUBLIC HEALTH RELEVANCE: The efficacy of drugs currently used to treat chronic disorders of the central nervous system, such as Parkinson's disease, epilepsy, addiction, pain and depression, often is limited by side effects or the development of tolerance. Understanding the mechanisms that regulate drug action could lead to the identification of novel means of augmenting drug efficacy or specificity. This project advances this goal by elucidating new mechanisms controlling the action of protein complexes that regulate the action of cocaine and morphine, and probably other drugs that act via modulatory G protein- coupled receptors in the nervous system.

描述（由申请人提供）：该项目的长期目标是定义控制 G 蛋白偶联受体 (GPCR) 信号转导的机制。本申请的重点是一类发育调节、视觉和神经系统特异性的 G23 二聚体，其由 G25 组成，G25 是分歧最大且了解最少的 G2 家族成员，与 RGS7 任何成员的 G3 样结构域结合（ R7) G 蛋白调节剂家族。 R7-G25 异二聚体结合 R7BP，一种新型棕榈酰化 SNARE 样蛋白。本申请的中心假设是，R7BP 上的棕榈酸循环控制着 R7-G25-R7BP 复合物作为神经元结构和功能调节剂的定位和功能。该项目将通过采用跨学科的细胞、分子和电生理学检测来测试这一假设，以解决以下具体目标：1) 确定调节 R7BP 棕榈酸酯循环和初级神经元运输的机制； 2)确定R7BP如何调节R7-G25复合物调节突触传递的能力以及棕榈酰化在这些过程中的作用； 3) 确定 R7-G25-R7BP 复合物调节神经元发育、可塑性和形态发生的信号传导机制。 公共卫生相关性：目前用于治疗中枢神经系统慢性疾病（例如帕金森病、癫痫、成瘾、疼痛和抑郁症）的药物的疗效通常受到副作用或耐受性的限制。了解调节药物作用的机制可能有助于识别增强药物功效或特异性的新方法。该项目通过阐明控制蛋白质复合物作用的新机制来推进这一目标，这些蛋白质复合物调节可卡因和吗啡以及可能通过神经系统中的调节性 G 蛋白偶联受体发挥作用的其他药物。